What is the appropriate work‑up for a patient with an absolute lymphocyte count of 495 cells/µL (lymphopenia)?

Work-up for Absolute Lymphocyte Count of 495 cells/µL

An absolute lymphocyte count of 495 cells/µL represents grade 3 lymphopenia requiring weekly CBC monitoring, CMV screening, and targeted investigation only if accompanied by recurrent infections, progressive cytopenias, lymphadenopathy, or constitutional symptoms. 1

Severity Classification and Immediate Actions

Your patient has grade 3 lymphopenia (ALC 250-499 cells/µL), which sits between moderate and severe immunosuppression. 1

Initial monitoring protocol:

• Weekly CBC with differential to track trajectory 1
• CMV screening via PCR or antigenemia assay 2, 1
• Focused physical examination for lymphadenopathy, hepatosplenomegaly 1
• Document any fever, night sweats, weight loss, or infection history 1

Essential History to Obtain

Medication review - specifically ask about:

• Corticosteroids, chemotherapy agents, fludarabine, antithymocyte globulin 1
• Recent radiation exposure 2

Infection history:

• Frequency and severity of recent infections 1
• Any opportunistic infections (Pneumocystis, CMV, fungal) 2
• HIV and viral hepatitis risk factors 1

Autoimmune and nutritional assessment:

• Personal or family history of autoimmune disease 1
• Signs of malnutrition, malabsorption 2, 1

Physical Examination Focus

• All lymph node regions - cervical, supraclavicular, axillary, inguinal 1
• Abdominal examination for splenomegaly or hepatomegaly 1
• Constitutional symptoms - fever, night sweats, unexplained weight loss 1

Core Laboratory Work-up

Complete blood count analysis:

• Manual differential to evaluate all cell lines 1
• Peripheral blood smear for lymphocyte morphology and atypical cells 1
• Critical: Assess for other cytopenias (anemia, thrombocytopenia) 1

Flow cytometry immunophenotyping of peripheral blood:

• CD5, CD19, CD20, CD23 (B-cell markers) 1, 3
• CD3, CD4, CD8 (T-cell markers) 1, 3
• Surface light-chain restriction (kappa/lambda) to assess clonality 1, 3
• Note: This excludes chronic lymphocytic leukemia, which requires ≥5,000 cells/µL by definition 1, 3

Viral and nutritional testing:

• HIV serology 1
• Hepatitis B and C serologies 1
• CMV PCR or antigenemia 2, 1
• Vitamin B12, folate, iron studies 1

Optional imaging:

• Chest radiograph to evaluate for thymoma 1

When to Escalate Investigation

Bone marrow biopsy is indicated if:

• Additional cytopenias develop (anemia or thrombocytopenia) 1
• New lymphadenopathy or organomegaly appears 1
• Progressive decline in lymphocyte count over serial measurements 1
• Recurrent or opportunistic infections occur 1

Management Based on Findings

If stable grade 3 lymphopenia without other abnormalities:

• Continue weekly CBC monitoring 1
• Repeat CMV screening as clinically indicated 1
• No antimicrobial prophylaxis needed at this level 1
• Patient may continue normal activities with heightened infection vigilance 1

If lymphopenia worsens to grade 4 (<250 cells/µL):

• Initiate Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) 2, 1
• Add Mycobacterium avium complex prophylaxis (azithromycin) 2, 1
• Consider discontinuing any lymphocyte-depleting medications 1

If CD4 count <200 cells/µL:

• Begin trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis once total WBC >3.0 × 10⁹/L or ANC >1.5 × 10⁹/L 2
• Continue prophylaxis until CD4 count rises above 200 cells/µL 2

Critical Pitfalls to Avoid

• Do not confuse lymphopenia with lymphocytosis - CLL requires lymphocytosis ≥5,000 cells/µL, not lymphopenia 1, 3, 4
• Do not over-investigate stable lymphopenia - bone marrow biopsy is not justified without progressive decline, other cytopenias, or clinical deterioration 1
• Do not start prophylactic antibiotics prematurely - antimicrobial prophylaxis at grade 3 lymphopenia offers no benefit and risks adverse effects 1
• Do not miss radiation exposure history - a 50% decline in ALC within 24-48 hours suggests potentially lethal radiation exposure requiring specialized management 2

Special Consideration: Radiation Exposure

If radiation exposure is suspected, lymphopenia kinetics serve as biodosimetry. A rapid 50% decline within 24 hours followed by further decline at 48 hours characterizes potentially lethal exposure requiring immediate hematology consultation. 2